title: Bispecific molecules directed to the Fc receptor for IgA (Fc alpha RI, CD89) and tumor antigens efficiently promote cell-mediated cytotoxicity of tumor targets in whole blood.
abstract: The FcR for IgA (Fc alpha RI, CD89) is primarily expressed on cytotoxic immune effector cells. By chemically cross-linking F(ab') fragments of the FcR for IgA (Fc alpha RI)-specific mAb (A77) with tumor Ag-specific mAb (anti-HER2/neu and anti-epidermal growth factor receptor), we have developed bispecific molecules (BSM) that simultaneously bind to respective tumor Ags and Fc alpha RI-expressing effector cells in whole blood. These BSM mediated up to 55% of specific lysis of appropriate tumor Ag-expressing target cells (from a variety of tumors) with purified polymorphonuclear leukocytes, monocytes, or whole blood effector cells without preactivation with exogenous cytokines. To our knowledge, this is the first demonstration of Ab-dependent cell-mediated cytotoxic activity via Fc alpha RI in whole blood. Also, monocyte-derived macrophages mediated phagocytosis of HER2/neu-expressing tumor cells (>95% tumor cell loss). These BSM-mediated cytotoxic activities were completely inhibited by F(ab')2 of A77, demonstrating the specific role of Fc alpha RI as a trigger molecule. Furthermore, the binding of these BSM to monocytes or polymorphonuclear leukocytes in whole blood did not induce modulation of Fc alpha RI in the absence of the target Ag. Therefore, immune effector cells may be "armed" with Fc alpha RI-directed BSM in whole blood. These Fc alpha RI-directed BSM may offer new treatment options for various malignancies and other disease conditions.
authors.affiliation: Medarex, Inc., Annandale, NJ 08801, USA. yashdeo@injersey.com
authors.forename: Y M
authors.initials: YM
authors.lastname: Deo
authors.forename: K
authors.initials: K
authors.lastname: Sundarapandiyan
authors.forename: T
authors.initials: T
authors.lastname: Keler
authors.forename: P K
authors.initials: PK
authors.lastname: Wallace
authors.forename: R F
authors.initials: RF
authors.lastname: Graziano
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000097:blood / Q000276:immunology*; D001666:Binding Sites, Antibody; D006801:Humans; D007111:Immunity, Cellular; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D010954:Plasmacytoma; D011485:Protein Binding / Q000276:immunology; D011961:Receptors, Fc / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc